The cytolytic molecules Fas ligand and TRAIL are required for murine thymic graft-versus-host disease
Identifieur interne : 001510 ( Main/Merge ); précédent : 001509; suivant : 001511The cytolytic molecules Fas ligand and TRAIL are required for murine thymic graft-versus-host disease
Auteurs : Il-Kang Na [États-Unis, Allemagne] ; Sydney X. Lu [États-Unis] ; Nury L. Yim [États-Unis] ; Gabrielle L. Goldberg [États-Unis] ; Jennifer Tsai [États-Unis] ; Uttam Rao [États-Unis] ; Odette M. Smith [États-Unis] ; Christopher G. King [États-Unis] ; David Suh [États-Unis] ; Daniel Hirschhorn-Cymerman [États-Unis] ; Lia Palomba [États-Unis] ; Olaf Penack [États-Unis, Allemagne] ; Amanda M. Holland [États-Unis] ; Robert R. Jenq [États-Unis] ; Arnab Ghosh [États-Unis] ; Hien Tran [États-Unis] ; Taha Merghoub [États-Unis] ; Chen Liu [États-Unis] ; Gregory D. Sempowski [États-Unis] ; Melissa Ventevogel [États-Unis] ; Nicole Beauchemin [Canada] ; Marcel R. M. Van Den BrinkSource :
- The Journal of Clinical Investigation [ 0021-9738 ] ; 2009.
Abstract
Thymic graft-versus-host disease (tGVHD) can contribute to profound T cell deficiency and repertoire restriction after allogeneic BM transplantation (allo-BMT). However, the cellular mechanisms of tGVHD and interactions between donor alloreactive T cells and thymic tissues remain poorly defined. Using clinically relevant murine allo-BMT models, we show here that even minimal numbers of donor alloreactive T cells, which caused mild nonlethal systemic graft-versus-host disease, were sufficient to damage the thymus, delay T lineage reconstitution, and compromise donor peripheral T cell function. Furthermore, to mediate tGVHD, donor alloreactive T cells required trafficking molecules, including CCR9, L selectin, P selectin glycoprotein ligand-1, the integrin subunits αE and β7, CCR2, and CXCR3, and costimulatory/inhibitory molecules, including Ox40 and carcinoembryonic antigen-associated cell adhesion molecule 1. We found that radiation in BMT conditioning regimens upregulated expression of the death receptors Fas and death receptor 5 (DR5) on thymic stromal cells (especially epithelium), while decreasing expression of the antiapoptotic regulator cellular caspase-8–like inhibitory protein. Donor alloreactive T cells used the cognate proteins FasL and TNF-related apoptosis-inducing ligand (TRAIL) (but not TNF or perforin) to mediate tGVHD, thereby damaging thymic stromal cells, cytoarchitecture, and function. Strategies that interfere with Fas/FasL and TRAIL/DR5 interactions may therefore represent a means to attenuate tGVHD and improve T cell reconstitution in allo-BMT recipients.
Url:
DOI: 10.1172/JCI39395
PubMed: 19955659
PubMed Central: 2798682
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<author><name sortKey="Sempowski, Gregory D" sort="Sempowski, Gregory D" uniqKey="Sempowski G" first="Gregory D." last="Sempowski">Gregory D. Sempowski</name>
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<wicri:regionArea>Goodman Cancer Centre, Department of Biochemistry, Department of Medicine, and Department of Oncology, McGill University, Montreal, Quebec</wicri:regionArea>
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<author><name sortKey="Rao, Uttam" sort="Rao, Uttam" uniqKey="Rao U" first="Uttam" last="Rao">Uttam Rao</name>
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<author><name sortKey="Smith, Odette M" sort="Smith, Odette M" uniqKey="Smith O" first="Odette M." last="Smith">Odette M. Smith</name>
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</author>
<author><name sortKey="Suh, David" sort="Suh, David" uniqKey="Suh D" first="David" last="Suh">David Suh</name>
<affiliation wicri:level="2"><nlm:aff id="JCI39395">Department of Medicine and Immunology, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">États-Unis</country>
<wicri:regionArea>Department of Medicine and Immunology, Memorial Sloan-Kettering Cancer Center, New York, New York</wicri:regionArea>
<placeName><region type="state">État de New York</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Hirschhorn Cymerman, Daniel" sort="Hirschhorn Cymerman, Daniel" uniqKey="Hirschhorn Cymerman D" first="Daniel" last="Hirschhorn-Cymerman">Daniel Hirschhorn-Cymerman</name>
<affiliation wicri:level="2"><nlm:aff id="JCI39395">Department of Medicine and Immunology, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">États-Unis</country>
<wicri:regionArea>Department of Medicine and Immunology, Memorial Sloan-Kettering Cancer Center, New York, New York</wicri:regionArea>
<placeName><region type="state">État de New York</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Palomba, Lia" sort="Palomba, Lia" uniqKey="Palomba L" first="Lia" last="Palomba">Lia Palomba</name>
<affiliation wicri:level="2"><nlm:aff id="JCI39395">Department of Medicine and Immunology, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">États-Unis</country>
<wicri:regionArea>Department of Medicine and Immunology, Memorial Sloan-Kettering Cancer Center, New York, New York</wicri:regionArea>
<placeName><region type="state">État de New York</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Penack, Olaf" sort="Penack, Olaf" uniqKey="Penack O" first="Olaf" last="Penack">Olaf Penack</name>
<affiliation wicri:level="2"><nlm:aff id="JCI39395">Department of Medicine and Immunology, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">États-Unis</country>
<wicri:regionArea>Department of Medicine and Immunology, Memorial Sloan-Kettering Cancer Center, New York, New York</wicri:regionArea>
<placeName><region type="state">État de New York</region>
</placeName>
</affiliation>
<affiliation wicri:level="3"><nlm:aff id="JCI39395">Department of Hematology and Oncology, Charité, Berlin, Germany.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">Allemagne</country>
<wicri:regionArea>Department of Hematology and Oncology, Charité, Berlin</wicri:regionArea>
<placeName><region type="land" nuts="3">Berlin</region>
<settlement type="city">Berlin</settlement>
</placeName>
</affiliation>
</author>
<author><name sortKey="Holland, Amanda M" sort="Holland, Amanda M" uniqKey="Holland A" first="Amanda M." last="Holland">Amanda M. Holland</name>
<affiliation wicri:level="2"><nlm:aff id="JCI39395">Department of Medicine and Immunology, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">États-Unis</country>
<wicri:regionArea>Department of Medicine and Immunology, Memorial Sloan-Kettering Cancer Center, New York, New York</wicri:regionArea>
<placeName><region type="state">État de New York</region>
</placeName>
</affiliation>
<affiliation wicri:level="2"><nlm:aff id="JCI39395">Department of Immunology, Weill Cornell Graduate School of Medical Sciences, New York, New York, USA.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">États-Unis</country>
<wicri:regionArea>Department of Immunology, Weill Cornell Graduate School of Medical Sciences, New York, New York</wicri:regionArea>
<placeName><region type="state">État de New York</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Jenq, Robert R" sort="Jenq, Robert R" uniqKey="Jenq R" first="Robert R." last="Jenq">Robert R. Jenq</name>
<affiliation wicri:level="2"><nlm:aff id="JCI39395">Department of Medicine and Immunology, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">États-Unis</country>
<wicri:regionArea>Department of Medicine and Immunology, Memorial Sloan-Kettering Cancer Center, New York, New York</wicri:regionArea>
<placeName><region type="state">État de New York</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Ghosh, Arnab" sort="Ghosh, Arnab" uniqKey="Ghosh A" first="Arnab" last="Ghosh">Arnab Ghosh</name>
<affiliation wicri:level="2"><nlm:aff id="JCI39395">Department of Medicine and Immunology, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">États-Unis</country>
<wicri:regionArea>Department of Medicine and Immunology, Memorial Sloan-Kettering Cancer Center, New York, New York</wicri:regionArea>
<placeName><region type="state">État de New York</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Tran, Hien" sort="Tran, Hien" uniqKey="Tran H" first="Hien" last="Tran">Hien Tran</name>
<affiliation wicri:level="2"><nlm:aff id="JCI39395">Department of Medicine and Immunology, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">États-Unis</country>
<wicri:regionArea>Department of Medicine and Immunology, Memorial Sloan-Kettering Cancer Center, New York, New York</wicri:regionArea>
<placeName><region type="state">État de New York</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Merghoub, Taha" sort="Merghoub, Taha" uniqKey="Merghoub T" first="Taha" last="Merghoub">Taha Merghoub</name>
<affiliation wicri:level="2"><nlm:aff id="JCI39395">Department of Medicine and Immunology, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">États-Unis</country>
<wicri:regionArea>Department of Medicine and Immunology, Memorial Sloan-Kettering Cancer Center, New York, New York</wicri:regionArea>
<placeName><region type="state">État de New York</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Liu, Chen" sort="Liu, Chen" uniqKey="Liu C" first="Chen" last="Liu">Chen Liu</name>
<affiliation wicri:level="2"><nlm:aff id="JCI39395">Department of Pathology, Immunology and Laboratory Medicine, University of Florida College of Medicine, Gainesville, Florida, USA.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">États-Unis</country>
<wicri:regionArea>Department of Pathology, Immunology and Laboratory Medicine, University of Florida College of Medicine, Gainesville, Florida</wicri:regionArea>
<placeName><region type="state">Floride</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Sempowski, Gregory D" sort="Sempowski, Gregory D" uniqKey="Sempowski G" first="Gregory D." last="Sempowski">Gregory D. Sempowski</name>
<affiliation wicri:level="2"><nlm:aff id="JCI39395">Human Vaccine Institute, Duke University School of Medicine, Durham, North Carolina, USA.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">États-Unis</country>
<wicri:regionArea>Human Vaccine Institute, Duke University School of Medicine, Durham, North Carolina</wicri:regionArea>
<placeName><region type="state">Caroline du Nord</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Ventevogel, Melissa" sort="Ventevogel, Melissa" uniqKey="Ventevogel M" first="Melissa" last="Ventevogel">Melissa Ventevogel</name>
<affiliation wicri:level="2"><nlm:aff id="JCI39395">Human Vaccine Institute, Duke University School of Medicine, Durham, North Carolina, USA.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">États-Unis</country>
<wicri:regionArea>Human Vaccine Institute, Duke University School of Medicine, Durham, North Carolina</wicri:regionArea>
<placeName><region type="state">Caroline du Nord</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Beauchemin, Nicole" sort="Beauchemin, Nicole" uniqKey="Beauchemin N" first="Nicole" last="Beauchemin">Nicole Beauchemin</name>
<affiliation wicri:level="4"><nlm:aff id="JCI39395">Goodman Cancer Centre, Department of Biochemistry, Department of Medicine, and Department of Oncology, McGill University, Montreal, Quebec, Canada.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">Canada</country>
<wicri:regionArea>Goodman Cancer Centre, Department of Biochemistry, Department of Medicine, and Department of Oncology, McGill University, Montreal, Quebec</wicri:regionArea>
<orgName type="university">Université McGill</orgName>
<placeName><settlement type="city">Montréal</settlement>
<region type="state">Québec</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Van Den Brink, Marcel R M" sort="Van Den Brink, Marcel R M" uniqKey="Van Den Brink M" first="Marcel R. M." last="Van Den Brink">Marcel R. M. Van Den Brink</name>
<affiliation><nlm:aff>NONE</nlm:aff>
</affiliation>
</author>
</analytic>
<series><title level="j">The Journal of Clinical Investigation</title>
<idno type="ISSN">0021-9738</idno>
<idno type="eISSN">1558-8238</idno>
<imprint><date when="2009">2009</date>
</imprint>
</series>
</biblStruct>
</sourceDesc>
</fileDesc>
<profileDesc><textClass></textClass>
</profileDesc>
</teiHeader>
<front><div type="abstract" xml:lang="en"><p>Thymic graft-versus-host disease (tGVHD) can contribute to profound T cell deficiency and repertoire restriction after allogeneic BM transplantation (allo-BMT). However, the cellular mechanisms of tGVHD and interactions between donor alloreactive T cells and thymic tissues remain poorly defined. Using clinically relevant murine allo-BMT models, we show here that even minimal numbers of donor alloreactive T cells, which caused mild nonlethal systemic graft-versus-host disease, were sufficient to damage the thymus, delay T lineage reconstitution, and compromise donor peripheral T cell function. Furthermore, to mediate tGVHD, donor alloreactive T cells required trafficking molecules, including CCR9, L selectin, P selectin glycoprotein ligand-1, the integrin subunits α<sub>E</sub>
and β<sub>7</sub>
, CCR2, and CXCR3, and costimulatory/inhibitory molecules, including Ox40 and carcinoembryonic antigen-associated cell adhesion molecule 1. We found that radiation in BMT conditioning regimens upregulated expression of the death receptors Fas and death receptor 5 (DR5) on thymic stromal cells (especially epithelium), while decreasing expression of the antiapoptotic regulator cellular caspase-8–like inhibitory protein. Donor alloreactive T cells used the cognate proteins FasL and TNF-related apoptosis-inducing ligand (TRAIL) (but not TNF or perforin) to mediate tGVHD, thereby damaging thymic stromal cells, cytoarchitecture, and function. Strategies that interfere with Fas/FasL and TRAIL/DR5 interactions may therefore represent a means to attenuate tGVHD and improve T cell reconstitution in allo-BMT recipients.
</p>
</div>
</front>
</TEI>
</record>
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